Relating tissue/organ energy expenditure to metabolic fluxes in mouse and human: experimental data integrated with mathematical modeling

Abstract

Mouse models of human diseases are used to study the metabolic and physiological processes leading to altered whole-body energy expenditure (EE), which is the sum of EE of all body organs and tissues. Isotopic techniques, arterio-venous difference of substrates, oxygen, and blood flow measurements can provide essential information to quantify tissue/organ EE and substrate oxidation. To complement and integrate experimental data, quantitative mathematical model analyses have been applied in the design of experiments and evaluation of metabolic fluxes. In this study, a method is presented to quantify the energy expenditure of the main mouse organs using metabolic flux measurements. The metabolic fluxes and substrate utilization of the main metabolic pathways of energy metabolism in the mouse tissue/organ systems and the whole body are quantified using a mathematical model based on mass and energy balances. The model is composed of six organ/tissue compartments: brain, heart, liver, gastrointestinal tract, muscle, and adipose tissue. Each tissue/organ is described with a distinct system of metabolic reactions. This model quantifies metabolic and energetic characteristics of mice under overnight fasting conditions. The steady-state mass balances of metabolites and energy balances of carbohydrate and fat are integrated with available experimental data to calculate metabolic fluxes, substrate utilization, and oxygen consumption in each tissue/organ. The model serves as a paradigm for designing experiments with the minimal reliable measurements necessary to quantify tissue/organs fluxes and to quantify the contributions of tissue/organ EE to whole-body EE that cannot be easily determined currently.

Keywords: Energy metabolism; flux balance analysis; metabolic pathway fluxes; oxygen consumption; substrate utilization.

Figure 1.

(A) Essential model inputs and equations for estimating computational outputs; (B) Whole‐body systems:Venous (gray arrows) and arterial blood (black arrows) leaving/going to the organ/tissue systems, respectively. RQ is respiratory quotient; VO₂ and VCO₂ are oxygen consumption and carbon dioxide release rates respectively; CHO and FAT are rates of carbohydrate and fat utilization.

Figure 2.

General metabolic pathways in whole‐body model. Eight substrates connected with open arrays are transported between tissue and blood. While gray arrows are common pathways in all tissues, black arrows are tissue‐specific pathways. The pathways marked with (*) are composed of several reaction steps but lumped into one step in this model. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ACoA, acetyl CoA; AA, amino acids; GLC, glucose; G6P, glucose‐6‐phosphate; GAP, glyceraldehyde‐3‐phosphate; GLR, glycerol; GRP, glycerol‐3‐phosphate; GLY, glycogen; FFA, free fatty acid; LAC, lactate; PYR, pyruvate; TG, triglycerides.

Figure 3.

Map for tissue‐specific metabolic pathways. In addition to the common pathways shown in Figure 2, each tissue has different kinds of metabolic pathways. Blank filled with gray color means the existence of the corresponding pathway.

Figure 4.

(A) Body composition; (B) Comparison of whole‐body VO₂ of the HRS/J mouse strain between simulated and experimental data obtained at 23° and 30°C.

Figure 5.

Sensitivity analysis. The effect of variation (±25% from the base case value) of ϕ_G6P→GLY in liver (A), Upt_GLR in liver (B), Rel_LAC, in skeletal muscle (C), and simultaneous variation (±25% from the base case value) of Rel_FFA and Rel_GLR in adipose tissue (D) on carbohydrate and fat utilization.

Figure 8.

The model equations were solved using the function fsolve in MATLAB. Some of the data inputs were highlighted in bold font in the flux balance diagram. The other data inputs are, RQ: 0.72; EE: 225.7 10⁻⁵ kcal min⁻¹; CE^CHO: 16.8 10⁻⁹ kcal nmol⁻¹; CE^FAT: 16.6 10⁻⁹ kcal nmol⁻¹; All metabolic fluxes are in nmol min⁻¹.